CN101309707A - Compositions comprising lipoxygenase inhibitors and cyclodextrin - Google Patents

Compositions comprising lipoxygenase inhibitors and cyclodextrin Download PDF

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Publication number
CN101309707A
CN101309707A CNA2006800426101A CN200680042610A CN101309707A CN 101309707 A CN101309707 A CN 101309707A CN A2006800426101 A CNA2006800426101 A CN A2006800426101A CN 200680042610 A CN200680042610 A CN 200680042610A CN 101309707 A CN101309707 A CN 101309707A
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lipoxygenase inhibitor
cyclodextrin
beta
schardinger dextrin
concentration
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詹姆斯·E·基普
普拉莫德·古普塔
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Baxter Healthcare SA
Baxter International Inc
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Baxter Healthcare SA
Baxter International Inc
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Abstract

The present invention is directed to formulations of inclusion complexes of lipoxygenase inhibitors and cyclodextrins having a therapeutically effective concentration of the lipoxygenase inhibitor, methods of making the same and methods of treating disease states using the same. Forming cyclodextrin complexes permits the enhancement of the aqueous solubility of lipoxygenase inhibitors which allows higher concentrations of the lipoxygenase in solution. Aqueous formulations of lipoxygenase inhibitors-cyclodextrin complexes are suitable for parenteral or oral administration for treating and/or preventing inflammatory disease states. The aqueous formulations can be lyophilized to prolong storage stability, assist in oral administration and/or provide for convenient and economical packaging.

Description

The compositions that contains lipoxygenase inhibitor and cyclodextrin
The application requires the priority of the U.S. Provisional Patent Application 60/736,980 of submission on November 15th, 2005.
Background of invention
The present invention relates to contain the compositions of lipoxygenase inhibitor and cyclodextrin, have the lipoxygenase inhibitor of the lipoxygenase inhibitor for the treatment of valid density and the bag of cyclodextrin and reply compound and pharmaceutical composition thereof by letter, the bag that manufacturing has the cyclodextrin of lipoxygenase inhibitor of treatment valid density and a lipoxygenase inhibitor is replied the method for the preparation of compound by letter, and the bag that uses the cyclodextrin of the lipoxygenase inhibitor with treatment valid density and lipoxygenase inhibitor is replied the method that the preparation of compound is treated by letter.Especially, the bag that the present invention relates to have the beta-schardinger dextrin-or derivatives thereof of lipoxygenase inhibitor of treatment valid density and 5-lipoxygenase inhibitor is replied the preparation of compound by letter, bag with the beta-schardinger dextrin-or derivatives thereof of lipoxygenase inhibitor of treatment valid density and 5-lipoxygenase inhibitor is replied the preparation of compound by letter, the bag that manufacturing has the beta-schardinger dextrin-or derivatives thereof of lipoxygenase inhibitor of treatment valid density and a 5-lipoxygenase inhibitor is replied the method for the preparation of compound by letter, and the bag that uses the beta-schardinger dextrin-or derivatives thereof of the lipoxygenase inhibitor with treatment valid density and 5-lipoxygenase inhibitor is replied the method that the preparation of compound is treated by letter.These preparations can be manufactured into aqueous solution, are used for for example using by parenteral or oral route, perhaps also can manufacture exsiccant form.Drying agent can redissolve and be used for administration, perhaps also can be further processed, be used to include but not limited in parenteral, oral, pulmonary, eye, nasal cavity, rectum, vagina, ear, surface, buccal, transdermal, intravenous, intramuscular, subcutaneous, intradermal, ophthalmic, the brain, in the lymph gland, in the intraarticular, sheath and the intraperitoneal route of administration.
Lipoxidase has been played the part of the key player in numerous disease, comprise for example asthma, rheumatic arthritis, gout, psoriasis, allergic rhinitis, Crohn disease (Crohn ' s disease), respiratory distress syndrome, chronic obstructive pulmonary disease, acne, atherosclerosis, aortic aneurysm, sickle-cell disease (sickle cell disease), acute lung injury, ischemia/reperfusion injury, nasal polyp and/or inflammatory bowel.Therefore, suppress the active chemical compound of lipoxidase and can be used for treating and/or preventing these diseases.This draw for reference to and constituted the United States Patent (USP) 4 of the part of this paper, 873,259,4,992,464 and 5,250,565 disclose some lipoxygenase inhibitor, particularly suppress the method for the pharmaceutical preparation of the chemical compound of 5-and/or 12-lipoxidase, the chemical compound that suppresses N-hydroxyurea 5-and/or 12-lipoxidase, the chemical compound of making inhibition 5-and/or 12-lipoxidase and 5-and/or 12-lipoxygenase inhibitor.A kind of such N-hydroxyurea lipoxygenase inhibitor is commonly called zileuton (zileuton).The zileuton of Orally administered 600mg dosage form is used to treatment of asthma.
Zileuton has the chemical constitution of showing down:
Figure A20068004261000101
Zileuton can be used as the racemic mixture (about 50: 50) of R (+) and S (-) enantiomer.The isomer of zileuton and the application in the active inhibition of lipoxidase thereof also are described.This draw for reference to and the U.S. Patent No. 5,629,337 that constituted the part of this paper the application of optically pure (-)-zileuton in the active inhibition of lipoxidase disclosed.This draw for reference to and the WO 94/26268 that constituted the part of this paper the application of optically pure (+)-zileuton in the active inhibition of lipoxidase disclosed.
Some N-hydroxyurea 5-and/or the low solubility of 12-lipoxygenase inhibitor in water have stoped these useful reagent when treating the application widely that can bring into play when effective prepared at concentrations becomes water soluble preparation.For example zileuton dissolves in methanol and ethanol, is slightly soluble in acetonitrile, in fact is insoluble to hexane and water (water solubility is 0.08-0.14mg/ml in the time of 25 ℃).Except dissolubility was low, zileuton and other possible N-hydroxyurea lipoxygenase inhibitor were anticipated in the aqueous solution when in room temperature storage during the long period being chemically unstable [insertion list of references].Degraded is with the specificity hydronium(ion)-or water-catalytic hydrolysis is consistent, and carbamic acid is provided, and it loses carbon dioxide immediately, and the generation azanol is as shown below.
Figure A20068004261000111
For zileuton, do not observe buffer agent catalysis.Acid when using 25 ℃-and water-catalytic speed constant, definite false one-level rate constant is about 7.8x10 in about 3.5 to about 7.5 pH scope -5h -1Under the situation of optimum pH 5.6, the shelf life of 10% drug loss that calculates is 57.3 days.The pH-velocity contour of determining according to speed data at 25 ℃ is presented among Fig. 1.
Increase 5-and/or 12-lipoxygenase inhibitor for example the dissolubility of zileuton can cause the increase of curative effect of medicine and the enhancing that treatment is used.For example, the aqueous solution of lipoxygenase inhibitor with treatment valid density can be formulated into ready-made, injectable, for example intravenous push or inject.In addition, liquid composite can be prepared into has higher lipoxygenase inhibitor concentration, is used for diluting before injection subsequently.Injectable lipoxygenase inhibitor preparation makes it can be used for the treatment of condition of illness widely.
In case prepared the liquid composite of lipoxygenase inhibitor, can prepare solid concentrates by known method with treatment valid density.When injection, these soluble solid concentrates can be dissolved then.These solid concentrates can also be prepared, to produce single agent form, for example tablet, capsule, lozenge, suppository etc.
Therefore, for the lipoxygenase inhibitor with treatment valid density, be used for safe parenteral and/or Orally administered 5-and/or 12-lipoxygenase inhibitor solubility or liquid composite, particularly have the treatment valid density the 5-lipoxygenase inhibitor, be used for parenteral administration solubility or liquid composite, exist demand.In addition, for the effective concentration of the required treatment of parenteral can be provided and do not produce by the solubility of the 5-of the caused side effect of unwanted high concentration excipient and/or 12-lipoxygenase inhibitor or liquid composite, also exist demand.
The invention summary
The bag that the present invention relates to contain lipoxygenase inhibitor and cyclodextrin is replied the compositions of compound by letter.
In another embodiment of the invention, the pharmaceutical composition that provides the bag that contains lipoxygenase inhibitor and cyclodextrin to reply compound by letter, wherein lipoxygenase inhibitor exists to treat effective concentration.
In another embodiment of the invention, provide the bag that contains lipoxygenase inhibitor and cyclodextrin to reply the pharmaceutical composition of compound by letter, wherein lipoxygenase inhibitor exists to treat effective concentration, and cyclodextrin is selected from alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin and derivant thereof.
In another embodiment of the invention, the pharmaceutical composition that provides the bag that contains lipoxygenase inhibitor and beta-schardinger dextrin-or derivatives thereof to reply compound and pharmaceutically useful excipient by letter, wherein lipoxygenase inhibitor exists to treat effective concentration.
In another embodiment of the invention, the pharmaceutical composition that provides the bag that contains lipoxygenase inhibitor and cyclodextrin to reply compound and pharmaceutically useful excipient by letter, wherein lipoxygenase inhibitor exists to treat effective concentration.
In another embodiment, the pharmaceutical composition that provides the bag that contains zileuton and beta-schardinger dextrin-to reply compound and pharmaceutically useful excipient by letter, wherein zileuton exists to treat effective concentration.
In another embodiment of the invention, the parenteral administration that provides the bag that contains lipoxygenase inhibitor and cyclodextrin to reply compound by letter, wherein lipoxygenase inhibitor exists to treat effective concentration.
In another embodiment of the invention, provide the bag that contains lipoxygenase inhibitor and cyclodextrin to reply the drying agent of compound by letter, wherein bag is replied compound by letter and is had the dissolubility of 0.2mg/mL at least, and lipoxygenase inhibitor exists to treat effective concentration.
In another embodiment of the invention, provide the bag of making 5-lipoxygenase inhibitor and beta-schardinger dextrin-to reply the method for the aqueous solution of compound by letter, comprise the following steps: to prepare aqueous buffer; Beta-cyclodextrin derivative is dissolved in the buffer solution; And in beta-cyclodextrin derivative and buffering solution, add the 5-lipoxygenase inhibitor.
In another aspect of the present invention, the pharmaceutical composition that contains lipoxygenase inhibitor and cyclodextrin by using is provided, treatment suffers from the mammiferous method of the disease of lipoxidase and/or the active mediation of leukotriene, and wherein said lipoxygenase inhibitor exists to treat effective lipoxygenase inhibitor concentration.
Description of drawings
Fig. 1 has shown the degradation reaction of zileuton in aqueous solution.
Fig. 2 has shown the pH-velocity contour of zileuton under 25 ℃.
Detailed Description Of The Invention
Unless indicate especially, singulative used herein comprised refer to the plural number of object.
Determine that the increase of the required dissolving of 5-and/or 12-lipoxygenase inhibitors can realize by replying compound by letter with cyclodextrin formation bag. Cyclodextrin has carried out detailed description by F.Schardinger, and in many documents early cyclodextrin is called Schardinger ' s dextrin. Cyclodextrin is the oligosaccharides of ring-type, has oh group at outer surface, at the center hole is arranged. The orientation of this kind ring-type provides the taper structure of brachymemma, outside hydrophilic, inner close fat.
The most common cyclodextrin be α-, β-and gamma-cyclodextrin, respectively by 6,7 with are connected the glucose unit of a α-Isosorbide-5-Nitrae-connection and consist of. The quantity of these unit has determined the size in hole.
Cyclodextrin can form bag into the hole and replies compound by letter by whole molecule or its some part are received with hydrophobic molecule. It is how good that the stability of the compound that forms depends on that the coupling in the hole of foreign molecules and cyclodextrin has. The composition that contains lipoxygenase inhibitors and cyclodextrin can comprise the bag of lipoxygenase inhibitors and cyclodextrin and reply compound by letter, and does not consist of lipoxygenase inhibitors and cyclodextrin that bag is replied the part of compound by letter.
α-, β-and gamma-cyclodextrin have limited water-solublely, and when by drug administration by injection, demonstrate some toxicity. For example, although beta-schardinger dextrin-and many medicines form the most stable compound, it is water-soluble that they have minimum cyclodextrin. Therefore, in order to overcome these shortcomings, the structure of cyclodextrin is carried out chemical modification, had the safer cyclodextrine derivatives of dissolving property increase with generation. Modification generally is one or more the carrying out in 2,3 or 6 oh groups. Cyclodextrine derivatives for example is being described in the United States Patent(USP) Nos. 5,134,127,5,376,645,5,571,534,5,874,418,6,046,177 and 6,133,248, and its content is drawn at this and is reference, and as the part of this paper. Mean to comprise not at term used herein " cyclodextrin " cyclodextrin modified with and the derivative of chemical modification.
Although α-, β-and gamma-cyclodextrin can be used for and 5-and/or 12-lipoxygenase inhibitors form compound, preferred cyclodextrin is β-and gamma-cyclodextrin, more preferably beta-schardinger dextrin-. Preferred beta-schardinger dextrin-comprises the beta-schardinger dextrin-that 2-hydroxyl propyl group-beta-schardinger dextrin-and sulphur derives for butyl (for example description being arranged in 5,134,127,5,376,645,5,874,418,6,046,177 and 6,133,248). The beta-schardinger dextrin-that a kind of such sulphur is derived for butyl is that sulphur is for butyl ether (7)-β-cyclodextrin. By CyDex, sell with trade name CAPTISOL (" CAPTISOL cyclodextrin ") by Inc. company for butyl ether (7)-beta-schardinger dextrin-for sulphur.
Preferred 5-and/or 12-lipoxygenase inhibitors are the types with molecular formula of following formula (I):
Figure A20068004261000151
R wherein1Be selected from H, C1-C4 alkyl, C2-C4 alkene base and NR2R 3, R wherein2And R3Be selected from independently of one another H, C1-C4 alkyl and hydroxyl, but R2And R3Be not hydroxyl simultaneously;
X wherein is oxygen, sulphur, SO2Or NR4, R wherein4Be selected from H, C1-C6 alkyl, C1-C6 alkane acyl group (aroyl), aroyl and alkane sulfonyl;
A is selected from C1-C6 alkylidene and C2-C6 alkenylene;
N is 1-5;
Each Y is independently selected from H, halogen, hydroxyl, cyano group, haloalkyl, C1-C12 alkyl, C2-C12 thiazolinyl, C1-C12 alkoxyl, C3-C8 cycloalkyl, C1-C8 alkylthio, aryl, aryloxy group, aroyl, C1-C12 aralkyl, C2-C12 arylalkenyl, C1-C12 aralkoxy and C1-C12 virtue thio alkoxy, and substituent group wherein is selected from halogen, nitro, cyano group, C1-C12 alkyl, alkoxyl and haloalkyl;
Z is oxygen or sulfur; And
M is hydrogen, pharmaceutically useful cation, aroyl or C1-C12 alkanoyl.
Substituent group Y and linking group A can be connected on any suitable position of two rings.
In another embodiment, 5-and/or 12-lipoxygenase inhibitor are the types with molecular formula (II):
Figure A20068004261000161
R wherein 5Be C1 or C2 alkyl or NR 6R 7, R wherein 6And R 7Be independently selected from H and C1 or C2 alkyl; B is CH 2Or CHCH 3W is oxygen or sulfur.
Term used herein " alkylidene " is meant the linking group of straight or branched, for example-and CH 2-,-C (CH 3) 2-,-CH (C 2H 5)-,-CH 2CH 2-,-CH 2CHCH 3-,-C (CH 3) 2-, C (CH 3) 2-, CH 2CH 2CH 2
Term used herein " alkenylene " is meant the undersaturated linking group of straight or branched, for example-CH=CH-,-CH=CHCH 2-, CH=CHCH (CH 3)-,-C (CH 3)=CHCH 2-,-CH 2CH=CHCH 2-,-C (CH 3) 2CH=CHC (CH 3) 2-.
Term used herein " alkyl " is meant the straight or branched group of 1 to 12 carbon atom, includes but not limited to methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, sec-butyl, isobutyl group and the tert-butyl group.
Term used herein " thiazolinyl " is meant the straight or branched unsaturated group of 2 to 12 carbon atoms, includes but not limited to vinyl, 1-acrylic, 2-acrylic, 2-methyl isophthalic acid-acrylic, 1-butylene base, crotyl.
Term used herein " cycloalkyl " is meant for example cyclic group of 3 to 8 carbon atoms, includes but not limited to cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl.
Term used herein " alkoxyl " is meant-OR 8, R wherein 8Be alkyl group, include but not limited to methoxyl group, ethyoxyl, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy etc.
Term used herein " alkylthio " is meant-SR 9, R wherein 9Be alkyl group, include but not limited to sulphomethyl, thio-ethyl, sulfo-isopropyl, sulfo-normal-butyl, sulfo-sec-butyl, sulfo-isobutyl group and the sulfo-tert-butyl group.
Term used herein " acyl group " is meant-COR 10, R wherein 10Be alkyl group, include but not limited to formoxyl, acetyl group, propiono, bytyry, isobutyryl and pivaloyl group.
Term used herein " alkoxy carbonyl group " is meant-COR 11, R wherein 11Be alkoxy base, include but not limited to methoxycarbonyl, ethoxy carbonyl, isopropoxy carbonyl, butoxy carbonyl, sec-butoxy carbonyl, isobutoxy carbonyl and tert-butoxycarbonyl.
Term used herein " aryl " is meant and replaces and unsubstituted carbocyclic ring and heteroaromatic group, substituent group wherein is selected from halogen, nitro, cyano group, alkyl, alkoxyl and haloalkyl, includes but not limited to phenyl, 1-or 2-naphthyl, 2-, 3-or 4-pyridine radicals, 2-and 3-furyl.
Term used herein " aroyl " is meant-COR 12, R wherein 12Be aromatic yl group, include but not limited to benzoyl, 1-naphthoyl and 2-naphthoyl.
Term used herein " aryloxy group " is meant-OR 13, R wherein 13Be aromatic yl group, include but not limited to phenoxy group, 1-naphthoxy and 2-naphthoxy.
Term used herein " aralkoxy " is meant-OR 14, R wherein 14It is aromatic alkyl group, include but not limited to benzyloxy (that is benzyloxy), 4-fluorobenzene methoxyl group, 1-benzene ethyoxyl, 2-benzene ethyoxyl, two benzyloxies, 1-naphthalene methoxyl group, 2-naphthalene methoxyl group, 9-fluorenes oxygen base, 2-, 3-or 4-pyridine methoxyl group and 2-, 3-, 4-, 5-, 6-, 7-, 8-quinolyl methoxyl group.
Term used herein " sulfo-aralkoxy " is meant-SR 15, R wherein 15Be aromatic alkyl group, include but not limited to thio phenyl methoxyl group (that is sulfo-benzyloxy), 4-fluorine thio phenyl methoxyl group, 1-thio phenyl ethyoxyl, 2-thio phenyl ethyoxyl, dithio benzyloxy and 1-sulfo-naphthalene methoxyl group.
Term used herein " aralkyl " is meant that aromatic yl group appends on the alkyl group, includes but not limited to benzyl (benzyl), 1-phenylethyl, 2-phenylethyl, 1-naphthyl ethyl and 2-pyridylmethyl.
Term used herein " arylalkenyl " is meant that aromatic yl group appends on the alkenyl group, includes but not limited to phenyl vinyl, 3-phenyl third-1-thiazolinyl, 3-phenyl third-2-thiazolinyl and 1-naphthyl vinyl.
Term used herein " alkyl sulphonyl " is meant-SO 2R 16, R wherein 16Be alkyl group, include but not limited to methyl sulphonyl, ethylsulfonyl and isopropyl sulfonyl.
Term used herein " halo " and " halogen " are meant from element fluorine, chlorine, the deutero-group of bromine or iodine.
Term used herein " haloalkyl " is meant the above-mentioned alkyl group that is replaced by one or more halogens, includes but not limited to chloro methyl, trifluoromethyl, 2,2,2-three chloroethyls etc.
Term " pharmaceutically useful cation " is meant avirulent cation, include but not limited to based on alkali metal or alkaline-earth metal, cation of sodium, lithium, potassium, calcium, magnesium etc. for example, and avirulent ammonium, quaternary ammonium and amine cation, include but not limited to ammonium, tetramethyl-ammonium, tetraethyl ammonium, methyl amine, dimethyl amine, Trimethylamine, triethylamine and ethylamine.
The bag of N-hydroxyurea 5-and/or 12-lipoxygenase inhibitor is replied the formation of compound by letter and is benefited, and has the treatment potentiality because this class lipoxygenase inhibitor has demonstrated under clinical settings.Specifically, preferred 5-lipoxygenase inhibitor, zileuton are used for oral administration treatment asthma by clinical approval.Zileuton has following chemical structural formula:
Figure A20068004261000191
Some lipoxygenase inhibitor described herein, comprise zileuton, contain one or more asymmetric centers, and therefore can produce enantiomer, diastereomer and other can be defined as according to the absolute stereo chemistry (R)-or (S)-stereoisomer form.The present invention means and has comprised all these possible isomers, comprises racemic mixture, optically pure form and intermediate mixture.Optically active (R)-and (S)-isomer can be used chiral synthon or Chirality Reaction reagent preparation, also can use routine techniques to split." isomer " is the different chemical compounds with same molecular formula." stereoisomer " is to be that atom is in the different isomer of spatial arrangement mode." enantiomer " is a pair of stereoisomer that can not eclipsed mirror image of being each other.1: 1 mixture of a pair of enantiomer is " racemization " mixture.Term " (±) " is used to represent racemic mixture in suitable place." diastereomer " is to have at least two asymmetric atoms but the stereoisomer of mirror image each other not each other.The absolute stereo chemistry is demarcated according to the R-S system of Cahn-Ingold-Prelog.When chemical compound was pure enantiomer, the spatial chemistry of each chiral carbon atom can be demarcated with R or S.The chemical compound of the fractionation of absolute configuration the unknown can be according to them to the direction of rotation of the linearly polarized light of sodium D-line wavelength and called after (+) or (-) (dextrorotation or left-handed).When chemical compound described herein contains olefinic double bonds or other asymmetric center of geometry,, mean this chemical compound and comprise E and two kinds of geometric isomers of Z unless specialize.Similarly, all tautomeric forms are also comprised.
The term of Shi Yonging " zileuton " has comprised ((±)-1-(1-benzo [b] thiophene-2-base ethyl)-1-hydroxyurea in this article, N-(1-benzo [b] thiophene-2-base ethyl)-(the S)-enantiomer of N-hydroxyurea or the optical voidness form of (-)-isomer are (in for example U.S. Patent No. 5, description is arranged) in 629,337, N-(1-benzo [b] thiophene-2-base ethyl)-(the R)-enantiomer of N-hydroxyurea or optical voidness form of (+)-isomer (for example among the WO 94/26268 description being arranged), described (S)-and (R)-isomer is with the blended mixture of any ratio between 1: 99 and 99: 1, and the multiform form of the zileuton of known at present or recent findings.
In one embodiment, the lipoxygenase inhibitor chemical compound is selected from optical voidness (-)-isomer of (±)-1-(1-benzo [b] thiophene-2-base ethyl)-1-hydroxyurea, N-(1-benzo [b] thiophene-2-base ethyl)-N-hydroxyurea and optical voidness (+)-isomer of N-(1-benzo [b] thiophene-2-base ethyl)-N-hydroxyurea.
In another embodiment of the invention, provide the bag that contains lipoxygenase inhibitor and cyclodextrin to reply the pharmaceutical composition of compound by letter with the lipoxygenase inhibitor for the treatment of valid density.The effective concentration of treatment used herein is meant that the concentration of the drug dose that provides causes the effect of the property alleviated, and needn't use the typical maximum volume that surpasses concrete route of administration when using with treatment or prevention inflammatory condition of illness to the experimenter.When for example using the intravenous push preparation, the concentration of lipoxygenase inhibitor is should be enough high, produces the dosage of alleviating the property effect to provide, and needn't use typical maximum volume above intravenous push simultaneously, be about 100mL.Conversely, dosage depends on many factors that the clinician need consider, for example age, body weight, diagnosis, disease stage etc. again.
In one embodiment, the pharmaceutical composition that provides the bag that contains lipoxygenase inhibitor and cyclodextrin to reply compound by letter, cyclodextrin wherein are selected from the group of alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin and derivant thereof and select.Bag is replied compound by letter and is preferably formed from 5-lipoxygenase inhibitor and beta-schardinger dextrin-or derivatives thereof.In another embodiment, this pharmaceutical composition contains the lipoxygenase inhibitor and the beta-schardinger dextrin-or derivatives thereof of structural formula (I), and lipoxygenase inhibitor wherein exists to treat effective amount.In another embodiment, pharmaceutical composition contains the lipoxygenase inhibitor and the beta-schardinger dextrin-or derivatives thereof of structural formula (II), and lipoxygenase inhibitor wherein exists to treat effective amount.Although the beta-schardinger dextrin-of many types can be used for forming complex, preferred beta-schardinger dextrin-is hydroxypropyl-beta-schardinger dextrin-and the deutero-beta-schardinger dextrin-of sulfo-butyl.It is that the bag of zileuton and sulfo-butyl ether (7)-beta-schardinger dextrin-is replied compound by letter that preferred lipoxygenase inhibitor and cyclodextrin bag are replied compound by letter.
Pharmaceutical composition described herein can be chosen wantonly and comprise one or more pharmaceutically useful excipient.Pharmaceutically useful excipient like this is being well-known in the art, and comprises for example combination of salt, surfactant, water-soluble polymer, antiseptic, antimicrobial, antioxidant, antifreezing agent, humidizer, thickening agent, osmotic pressure regulator, grinding agent (levigating agent), absorption reinforcing agent, penetration enhancers, pH regulator agent, adhesion agent, coloring agent, flavoring agent, diluent, emulsifying agent, suspending agent, solvent, cosolvent, buffer agent and these excipient.
The surfactant that is fit to can be selected from surfactant, aminoacid and the derivant thereof of ionic surface active agent, non-ionic surface active agent, zwitterionic surfactant, polymeric surfactant, phospholipid, biogenetic derivation, or the derivant of above-mentioned surfactant, combination or conjugate.Ionic surface active agent can be an anion or cationic.The amount of the surfactant that exists in the compositions is from about 0.01% to 10%w/v, preferably from about 0.05% to about 5%w/v.
The anion surfactant that is fit to includes but not limited to: alkylsulfonate; arylsulphonate; alkylphosphonic; phosphonate ester; potassium laurate; sodium lauryl sulfate; sodium lauryl sulphate; alkyl polyoxyethylene base sulfate; sodium alginate; dioctyl sodium sulfosuccinate; phosphatidic acid and salt thereof; sodium carboxymethyl cellulose; bile acid and salt thereof; cholic acid; deoxycholic acid; glycocholic acid; cholyltaurine and glycodesoxycholic acid, and carboxymethylcellulose calcium; stearic acid and salt thereof; calcium stearate; phosphate; sodium lauryl sulphate; carboxymethylcellulose calcium; sodium carboxymethyl cellulose; dioctyl sulfosuccinate; the dialkyl of sulfo-sodium succinate; sodium lauryl sulfate and phospholipid.
The cationic surfactant that is fit to includes but not limited to: quaternary ammonium compound; benzalkonium chloride; cetrimonium bromide; chitosan; lauryl dimethyl benzyl ammonium chloride; the fatty acyl carnitine hydrochlorate; the alkyl halide pyridine; hexadecylpyridinium chloride; cationic lipid; the polymethyl methacrylate trimethylammonium bromide; sulfonium compound (sulfonium compounds); polyvinylpyrrolidone-2-dimethyl aminoethyl dimethylaminoethyl acrylate methyl base sulfate; cetyl trimethyl ammonium bromide; phosphorus compound; quaternary ammonium compound; benzyl-two (2-chloroethyl) ethyl ammonium bromide; the cocos nucifera oil trimethyl ammonium chloride; the cocos nucifera oil trimethylammonium bromide; cocos nucifera oil methyl dihydroxy ethyl ammonium chloride; cocos nucifera oil methyl dihydroxy ethyl ammonium bromide; the decyl triethyl ammonium chloride; the decyl dimethyl hydroxyethyl ammonium chloride; decyl dimethyl ethoxy chlorination ammonium bromide; the C12-15-dimethyl hydroxyethyl ammonium chloride; C12-15-dimethyl ethoxy chlorination ammonium bromide; the coco dimethyl hydroxyethyl ammonium chloride; coco dimethyl ethoxy ammonium bromide; myristyl trimethyl methylsulfuric acid ammonium; lauryl dimethyl benzyl ammonium chloride; lauryl dimethyl benzyl ammonium bromide; lauryl dimethyl (ethyoxyl) 4 ammonium chloride; lauryl dimethyl (ethyoxyl) 4 ammonium bromide; N-alkyl (C12-18) dimethyl benzene ammonio methacrylate; N-alkyl (C14-18) dimethyl benzene ammonio methacrylate; single water N-Zephiramine chloride; dimethyl didecyl ammonium chloride; N-alkyl and (C12-14) dimethyl 1-naphthyl methyl ammonium chloride; trimethyl-ammonium halide; alkyl trimethyl ammonium salt; dialkyl group-dimethyl ammonium; lauryl trimethyl ammonium chloride; the alkylamidoalkyl alkyl dialkyl ammonium salt of ethoxylation; the trialkyl ammonium salts of ethoxylation; the dialkyl benzene dialkylammonium chloride; the N-DDAC; single water N-Zephiramine chloride; N-alkyl (C12-14) dimethyl 1-naphthyl methyl ammonium chloride; dodecyl dimethyl benzyl ammonium chloride; the dialkyl benzene alkyl ammomium chloride; lauryl trimethyl ammonium chloride; alkylbenzene methyl ammonium chloride; alkyl benzyl dimethyl ammonium bromide; the C12 trimethylammonium bromide; the C15 trimethylammonium bromide; the C17 trimethylammonium bromide; dodecyl benzyl triethyl ammonium chloride; diallyl dimethyl ammoniumchloride (DADMAC); alkyl dimethyl ammonium chloride; the alkyl dimethyl ammonium halide; three (cetyl) ammonio methacrylate; the decyl trimethylammonium bromide; dodecyl triethyl group ammonium bromide; Tetradecyl Trimethyl Ammonium Bromide; methyl trioctylphosphine ammonium chloride; " POLYQUAT 10 " (mixture of polymeric quaternary ammonium compound); tert-butyl group bromination ammonium; the benzyl trimethylammonium bromide; cholinester; benzalkonium chloride; oronain (stearalkonium chloride) draws in department; the cetyl pyridinium bromine; cetyl pyridinium chlorine; the haloid of quaternised polyoxy ethyl alkylamine; " MIRAPOL " (polyquaternary amine-2) " Alkaquat " (alkyl dimethyl benzyl ammonium chloride is produced by Rhodia); Fixanol; amine; amine salt; imide azolinium salt; protonated tetravalence acrylamide; methylated tetravalence polymer and cation guar gum; benzalkonium chloride; Dodecyl trimethyl ammonium chloride; the husky amine (poloxamines) of triethanolamine and pool Lip river.
The ionic surfactant pack that is fit to is drawn together but is not limited to: polyoxyethylene aliphatic alcohol ether; the polyoxyethylene sorbitan fatty acid ester; the alkyl polyoxyethylene sulfuric ester; polyoxyethylene fatty acid ester; sorbitan esters; glyceride; glyceryl monostearate; Polyethylene Glycol; polypropylene glycol; the polypropylene glycol ester; hexadecanol; cetostearyl alcohol (cetostearylalcohol); octadecanol; the aryl alkyl Aethoxy Sklerol; polyoxyethylene-polyoxypropylene copolymer; poloxamer (poloxamers); the husky amine (poloxamines) in pool Lip river; methylcellulose; hydroxylated cellulose; hydroxy methocel; hydroxypropyl cellulose; hydroxypropyl emthylcellulose; non-crystalline cellulose; polysaccharide; starch; starch derivatives; hetastarch; polyvinyl alcohol; polyvinylpyrrolidone; triethanolamine stearate; amine oxide; glucosan; glycerol; arabic gum; cholesterol; Tragacanth; glyceryl monostearate; cetostearyl alcohol (cetostearylalcohol); cetomacrogol (Cetomacrogol) emulsifing wax; sorbitan esters; polyoxyethylene alkyl ether; castor oil derivatives; the polyoxyethylene sorbitan fatty acid ester; Polyethylene Glycol; Myrj 45; hydroxypropyl cellulose; hydroxypropyl emthylcellulose; methylcellulose; hydroxyethyl-cellulose; hydroxypropylmethyl cellulose phthalate; noncrystalline cellulose; polyvinyl alcohol; polyvinylpyrrolidone; 4-(1; 1; 3; the 3-tetramethyl butyl) polymer of phenol and oxirane and formaldehyde; poloxamer (poloxamers); alkyl aryl polyether sulfonate; the mixture of sucrose stearate and sucrose distearate; to different Nonylphenoxy poly epihydric alcohol; capryl-N-methyl glucoside amide; n-decyl-β-D-pyranglucoside; n-decyl-β-D-pyrans maltoside; n-dodecyl-β-D-pyranglucoside; n-dodecyl-β-D-maltoside; oenanthyl-N-methyl glucoside amide; n-heptyl-β-D-pyranglucoside; n-heptyl-β-D-thioglycoside; n-hexyl-β-D-pyranglucoside; pelargonyl group-N-methyl glucoside amide; n-nonyl-β-D-pyranglucoside; caprylyl-N-methyl glucoside amide; n-octyl group-β-D-pyranglucoside; octyl group-β-D-sulfo-pyranglucoside; the PEG-cholesterol; the PEG-cholesterin derivative; the PEG-vitamin A; PEG-vitamin E, and the random copolymer of vinyl acetate and vinyl pyrrolidone.
Zwitterionic surfactant is electroneutral, but has partial positive charge and negative charge at this intramolecularly.The zwitterionic surfactant that is fit to includes but not limited to zwitterionic phospholipid.The phospholipid that is fit to comprises phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, DG phosphoethanolamine (for example two myristoyl phosphoglycerol ethanolamine (DMPE), two palmityl phosphoglycerol ethanolamine (DPPE), distearyl base glycerol phosphoethanolamine (DSPE), and dioleoyl phosphoglycerol ethanolamine (DOPE)).The mixture of phospholipids that comprises anion and zwitterionic phospholipid can be used for the present invention.Such mixture includes but not limited to lysophosphatide, lecithin or soybean phospholipid or its arbitrary combination.
The polymeric surfactant that is fit to includes but not limited to polyamide, in the poly-carbonic acid, poly-alkylene, poly alkylene glycol, polyalkylene oxide, poly-alkylene terephthalate, polyvinyl alcohol, polyvinylether, polyvinyl ester, polyvinylhalide, polyvinylpyrrolidone, polyglycolide, polysiloxanes, polyurethanes and copolymer thereof, alkylcellulose, hydroxy alkyl cellulose, cellulose ether, cellulose esters, celluloid, the polymer of acrylate and methacrylate, methylcellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, hydroxy butyl methyl cellulose, cellulose ethanoate, cellulose propionate, the cellulose acetate butyl ester, cellulosic phthalic acetate, carboxyethyl cellulose, cellulosic triacetate, the sulfate cellulose sodium salt, polymethyl methacrylate, polyethyl methacrylate, polybutyl methacrylate, polyisobutyl methacrylate, the own ester of polymethylacrylic acid, polymethylacrylic acid isodecyl ester, polylauryl methacrylate, the polymethylacrylic acid phenylester, polymethyl acrylate, the polyacrylic acid isopropyl ester, polyisobutyl acrylate, the polyacrylic acid stearyl, polyethylene, the polypropylene Polyethylene Glycol, poly(ethylene oxide), polyethylene terephthalate, polyvinyl alcohol, polyvinyl acetate, polrvinyl chloride polystyrene and polyvinylpyrrolidone.
The surfactant of the biogenetic derivation that is fit to comprises but is not limited to: lipoprotein, gelatin, casein, lysozyme, albumin, casein, heparin, hirudin or other albumen.
The buffer agent that is fit to includes but not limited to sodium hydroxide, hydrochloric acid, tris buffer agent, list, two, tricarboxylic acids and salt thereof, citrate buffer agent, phosphoric acid buffer agent, glycerol-1-phosphoric acid, glycerol-2-phosphoric acid, acetic acid, lactic acid, Tris, aminosaccharide, list, two and trialkylated amine, meglumine (N-methyl glucoside amine), and aminoacid.
Pharmaceutical composition described herein can be by several route of administration administrations, include but not limited in parenteral, oral, pulmonary, eye, nasal cavity, rectum, vagina, ear, surface, buccal, transdermal, intravenous, intramuscular, subcutaneous, intradermal, ophthalmic, the brain, in the lymph gland, in the intraarticular, sheath and the intraperitoneal route of administration.The route of administration of the compositions of using and dosage can determine by the professional and technical personnel, and do not need the dose response research of too much experiment together with standard.The correlation circumstance that need consider when making these decisions comprises the selection of the disease of being treated, the compositions of using, age, body weight and the reaction of individual patient and the seriousness of patient symptom.
The excipient that comprises in pharmaceutical composition of the present invention is selected according to required compositions route of administration in treatment is used.Therefore, the compositions that is designed to administration in mouth, tongue, Sublingual, cheek and the cheek can prepare by the method for knowing in the art, and does not need too much experiment, for example uses inert diluent or edible carrier.Compositions can be wrapped in the ' Yanming ' capsules for clearing or be compressed into tablet.Use purpose for oral medication, pharmaceutical composition of the present invention can mix excipient, uses with forms such as tablet, lozenge, capsule, elixir, outstanding agent, syrup, dried thin slice, chewing gum.
Solid dosage forms, for example tablet, pill and capsule also can contain one or more binding agents, filler, suspending agent, disintegrating agent, lubricant, sweeting agent, flavoring agent, antiseptic, buffer agent, humidizer, distintegrant, foaming agent and other excipient.Such excipient is well-known in the present technique field.The example of filler is single water and milk sugar, Lactis Anhydrous and various starch.The example of binding agent is the micro-crystalline cellulose (SMCC) of various celluloses and crosslinked polyvinylpyrrolidone, micro-crystalline cellulose, micro-crystalline cellulose and silication.The lubricant that is fit to comprises the reagent of the fluid ability that acts on compressed powder, for example silica sol, Pulvis Talci, stearic acid, magnesium stearate, calcium stearate and silica gel.The example of sweeting agent is any natural or synthetical sweeting agent, for example sucrose, xylitol, saccharin sodium, cyclohexyl-n-sulfonate, aspartame and acesulfame potassium (accsulfame K).The example of flavoring agent is chewing gum spice, fruit flavor etc.Examples of preservatives is potassium sorbate, methyl parahydroxybenzoate, propyl p-hydroxybenzoate, benzoic acid and salt thereof, other p-Hydroxybenzoate butyl p-hydroxybenzoate, alcohols ethyl or benzyl alcohol class, phenolic compound phenol or tetravalence chemical compound benzalkonium chloride for example for example for example for example.The diluent that is fit to comprises pharmaceutically useful inert filler, for example the mixture of micro-crystalline cellulose, lactose, dicalcium phosphate, saccharide and/or any above-mentioned substance.The example of diluent comprises for example single water and milk sugar of micro-crystalline cellulose, lactose, Lactis Anhydrous, dicalcium phosphate, mannitol, starch, sorbitol, sucrose and glucose.The distintegrant that is fit to comprises corn starch, potato starch, corn starch and modified starch, croscarmellose sodium, crospolyvinylpyrrolidone, sodium starch glycollate (sodium starchglycolate) and their mixture.The example of foaming agent is the paired material of foaming, for example organic acid plus carbonate or bicarbonate.The organic acid that is fit to comprises for example citric acid, tartaric acid, malic acid, Fumaric acid, adipic acid, succinic acid and alginic acid and anhydride and salt.The carbonate and the bicarbonate that are fit to comprise for example sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, sodium glycine carbonate, L-lysine carbonate and arginine carbonate.In addition, only existence is foamed into the sour composition in the material.
Also can exist multiple other material as the peplos or the physical form of modifying medicament.For example, tablet can be used Lac, sugar or the two parcel.Syrup and elixir can also contain sucrose as sweeting agent except active component, p-hydroxybenzoic acid methyl ester and p-hydroxybenzoic acid propyl diester are as antiseptic, and dyestuff and flavoring agent be Fructus Pruni pseudocerasi or Fructus Citri tangerinae spice etc. for example.
Present invention includes by the compositions of nose approach to administration treatment effective dose.When using in this article, nasal administration or nose administration comprise the described compositions of the mucosal administration of patient's nasal passage or nasal cavity.When using in this article, be used for the pharmaceutical composition of nasal administration, with for example nasal spray, nasal drop, outstanding agent, gel, unguentum, cream or form of powder administration by well-known method preparation.The administration of compositions also can use nose tampon or nose sponge to fill in row.
For topical, the preparation that is fit to can comprise biocompatible oil, wax, gel, powder, polymer or other liquid or solid carrier.Such preparation can come administration by directly being applied to ill tissue, and for example, the liquid preparation that the treatment conjunctival tissue infects can dropwise be used patient's eyes, and perhaps the cream preparation can be applied to injured position.
Compositions of the present invention can parenteral, for example by in intravenous, intramuscular, the sheath or subcutaneous injection.Parenteral can be by mixing solution with compositions of the present invention or suspension is finished.Such solution or suspension also can comprise aseptic diluent for example water for injection, saline solution, nonvolatile oil, Polyethylene Glycol, glycerol, propylene glycol or other synthetic solvent.Parenteral administration also can comprise antibacterium reagent for example benzyl alcohol or methyl parahydroxybenzoate, and antioxidant is ascorbic acid or sodium sulfite for example, and chelating agen EDTA for example.Also can add for example acetate, citrate or phosphate and being used to reagent for example sodium chloride or the glucose of regulating osmotic pressure of buffer agent.Parenteral administration can be encapsulated in ampoule bottle, disposable syringe or the multi-agent medicine bottle that glass or plastics make.
Rectally comprises pharmaceutical composition is applied to rectum or large intestine.This can use suppository or enema to carry out.Suppository formulations can easily be made by the existing method in this area.For example, can be by glycerol being heated to about 120 ℃, pharmaceutical composition being dissolved in the glycerol, the glycerol of heating is mixed adding the water of purification then, then the mixture of heat is injected the suppository mould and prepare suppository formulations.
Transdermal administration comprises the absorption of compositions being passed through skin by skin.Preparation capable of permeating skin comprises plaster, unguentum, cream, gel, ointment etc.
Except ordinary meaning is said preparation described herein being used for its major function is to carry out any part, tissue or the organ of gas exchange with external environment condition, for purpose of the present invention, " pulmonary " also refers to comprise tissue or the vestibule, particularly nasal sinuses that is appended hereto respiratory tract.For pulmonary administration, consider to contain aerosol preparations, manual pump spray, aerosol apparatus or the pressurised metered medicament inhaler and the dry powder formulations of active agents.Such suitable preparation can also comprise other medicament, and for example antistatic additive is effective aerosol state to keep disclosed compositions.
Be used for aerocolloidal drug delivery device and comprise the aerosol can that is fit to that contains pharmaceutical aerosol preparation that has metering valve, and the driving device shell of transforming (actuator housing) is to hold jar and medicine is sent.Jar have headroom in the drug delivery device, occupy greater than about 15% of the cumulative volume of jar.Generally, be intended for use the polymer of pulmonary administration dissolved, suspend or be emulsified in the mixture of solvent, surfactant and propellant.Mixture is being maintained under the pressure in the jar with the metering valve sealing.
In one embodiment, the molar ratio of lipoxygenase inhibitor and cyclodextrin is preferably from about 10: 1 to about 1: 10.In another embodiment, the molar ratio of lipoxygenase inhibitor and cyclodextrin is preferably from about 5: 1 to about 1: 5.In another embodiment, ratio was from about 1: 1 to about 1: 5.The concentration of lipoxygenase inhibitor preferably from about 0.1mg/mL to about 200mg/mL, more preferably from about 1 to about 100mg/ml, more preferably from about 5mg/mL to about 50mg/mL, more preferably from about 8mg/mL to about 30mg/mL, the concentration of cyclodextrin preferably from about 4mM to about 900mM, more preferably from about 20mM to about 500mM, more preferably from about 30mM to about 200mM.In one embodiment, lipoxidase compositions of the present invention does not comprise buffer agent.In another embodiment, the also optional buffer agent that comprises of compositions.The buffer that is fit to includes but not limited to sodium hydroxide, hydrochloric acid, tris buffer, list, two, tricarboxylic acids and salt thereof, citrate buffer, phosphate buffer, glycerol-1-phosphate, glycerol-2-phosphate, acetate, lactate, Tris, aminosaccharide, list, two and trialkylated amine, meglumine (N-methyl glucoside amine), succinate, benzoate, tartrate, carbonate and amino acid whose solution.In preferred embodiments, buffer agent is a citrate buffer agent, more preferably under the situation citrate buffer agent concentration from about 2mM to about 500mM.Compositions preferably has from about 3 to about 9 pH.Compositions preferably is suitable for parenteral, more preferably is suitable for carrying out intravenous push or dense notes administration.
In another embodiment of the invention, provide and prepared the method that the bag that contains lipoxygenase inhibitor and cyclodextrin is replied the pharmaceutical composition of compound by letter, by the preparation aqueous buffer, cyclodextrin is dissolved in the buffer solution, and the adding lipoxygenase inhibitor carries out in cyclodextrin and buffering solution.
Under the preferable case, this method also comprises lipoxygenase inhibitor and cyclodextrin solution stirs and/or supersound process.Under the preferable case, this method comprises that also the pH with buffer solution adjusts to about 3 to about 9.In one embodiment, solution has the lipoxygenase inhibitor concentration from about 0.1mg/mL to about 200mg/mL.In another embodiment, the concentration of lipoxygenase inhibitor from about 5mg/mL to about 50mg/mL, in another embodiment, concentration from about 8mg/mL to about 30mg/mL.In another embodiment, cyclodextrin exists with the concentration from about 4mM to about 900mM, in another embodiment, from about 20mM to about 500mM, in another embodiment, from about 30mM to about 500mM.Preferred reducing agents is the citrate buffer agent of concentration from about 2mM to about 500mM.In another embodiment, the compositions that contains lipoxygenase inhibitor and cyclodextrin can contain lipoxygenase inhibitor and the cyclodextrin that is higher than above-described concentration.Such compositions can used preceding dilution to patient.
Preferred lipoxygenase inhibitor is N-hydroxyurea lipoxygenase inhibitor (for example among United States Patent(USP) Nos. 4,873,259,4,992,464,5,250,565 and 5,629,337 and the WO94/26268 description being arranged).In another embodiment, lipoxygenase inhibitor is a zileuton, and cyclodextrin is the beta-schardinger dextrin-or derivatives thereof.In a further preferred embodiment, cyclodextrin is sulfo-butyl ether (7)-beta-schardinger dextrin-.
Although when bag is replied compound by letter lipoxygenase inhibitor to be dissolved in the excessive cyclodextrin be possible forming, may wish to minimize the amount of the required cyclodextrin of dissolved substance, if when particularly solution will be by parenteral.
In one embodiment, the compound stoichiometry of drug-cyclodextrin complex is 1: 1.In other words, forgive at least 1 molecule/mole of cyclodextrin complex can contain to(for) per molecule/mole medicine.In order to determine the minimum of the cyclodextrin that dissolved substance is required, should carry out the mapping of medicine dissolution under the preferable case to cyclodextrin concentration.Push away in carrying out according to figure, can prepare the preparation that contains the required minimum cyclodextrin of dissolving lipoxygenase inhibitor.Because compound stoichiometry may change according to the complex of concrete 5-and/or 12-lipoxygenase inhibitor and cyclodextrin, therefore wish and to carry out such dissolubility mapping to every kind of concrete lipoxidase-cyclodextrin complexes.Dissolubility figure to zileuton-the CAPTISOL cyclodextrin complexes carries out has been described in the embodiment 1 of back.
Push away in carrying out according to the figure that describes among the embodiment 1, zileuton-the compound stoichiometry of CAPTISOL cyclodextrin embodiment is determined approximately is 1: 1.8.In other words, the minimum of the required CAPTISOL cyclodextrin of the about 1 mole of zileuton of dissolving is about 1.8 moles CAPTISOL cyclodextrin in about preferred concentration range of 5 to about 30mg/mL.As what notice above, excessive cyclodextrin can be used to dissolve lipoxygenase inhibitor, if when particularly cyclodextrin does not produce any side effect after administered formulation.
Although the initial pH value of solution of selecting is 5.5 concerning zileuton-CAPTISOL cyclodextrin complexes, situation may not be like this concerning other lipoxidase-cyclodextrin complexes.As described in embodiment 2, carried out the optimum pH scope of further test with the stability of definite maximization zileuton-CAPTISOL cyclodextrin complexes.For the optimum pH of determining other lipoxidase-cyclodextrin complexes also may also need to carry out such experiment.
Except the pharmaceutical solutions of preparation lipoxidase-cyclodextrin complexes, can also prepare solid preparation by existing method, for example lyophilization, spray drying and/or supercritical extraction.These solid concentrates can be suspended when injecting again then.In addition, these solid concentrates also can be by compound with manufacture order one dosage form, and for example the injection of tablet, capsule, lozenge, suppository, sugar coated tablet, capsule, ampoule (ampoule), suppository, slow releasing preparation, controlled release preparation, delayed release dosage system, pulsation delivery formulations, immediate release formulation, stomach are held and stayed preparation, effervescent tablet, dissolving tablet, oral liquid and spray formulation.Solid concentrates also can be mixed with the form that is selected from paster, the powder formulation that is used to suck, outstanding agent, unguentum and Emulsion.
These exsiccant preparations are preferred for having in the solution form lipoxygenase inhibitor-cyclodextrin complexes of bad long-time stability.
Exsiccant preparation may be provided as that similar health product supplier provided like that, it can be dissolved in the suitable dilution agent again, for example be suitable for the diluent of parenteral or oral administration.Same preparation can be by existing method preparation, using to the patient by various approach, such as but not limited to parenteral, oral, through lung, through eye, per nasal, per rectum, transvaginal, through ear, part, in cheek, transdermal, intravenous, intramuscular, subcutaneous, intradermal, ophthalmic, brain, in the lymph gland, in the intraarticular, sheath with the intraperitoneal route of administration.
In addition, exsiccant preparation can be dissolved again to produce the i.e. injectable preparation of usefulness, is preferably intravenous push or dense notes preparation.Cryodesiccated preparation can be dissolved into the dosage of high concentration again, can further be diluted when injection.In preferred embodiments, cryodesiccated preparation is dissolved again is used for parenteral, the concentration range that lipoxygenase inhibitor is provided is from about 0.1 to about 200mg/mL, more preferably from about 5 to about 50mg/mL, more preferably from about 8 to about 30mg/mL.
In order to prepare the drying solid of stabilisation, before lyophilization, can add filler for example mannitol, sorbitol, sucrose, starch, lactose, trehalose or Raffinose earlier.Solution can use any suitable lyophilization program to carry out lyophilization, for example:
At+25 ℃ of samples of packing into;
Arrive-45 ℃ at 1 hour internal cooling;
Kept 3.5 hours at-45 ℃;
Under 0.4mbar pressure through average 33 hours drying gradually temperature is increased to+15 ℃;
At last under 0.03mbar pressure+20 ℃ of dryings 10 hours;
Antifreezing agent: mannitol.
Under the preferable case,,, should carry out the solution freeze-thaw stability and the dsc analysis of pharmaceutical solutions for the lyophilization cycle that helps to select to be fit to for concrete lipoxygenase inhibitor-cyclodextrin complexes.
Sterilization can be finished by existing in the art several different methods, includes but not limited to heat sterilization, filtration and irradiation.Sterilization can be finished by the aseptic filtration of final lipoxidase-cyclodextrin solution preparation.Any then remaining step, for example lyophilization or packing all must be carried out under aseptic technique.Typical aseptic filtration method for example comprises that at first the filter by 3.0 microns carries out pre-filtering, filters by 0.45 micron particulate filter then, filters by two multiple membrane filters of 0.2 micron then.
No matter lipoxygenase inhibitor-cyclodextrin formulations is as pharmaceutical solutions or freeze-dried preparation, can by heat sterilization, irradiation or other known sterilizing methods for example autoclaving sterilize.
Pharmaceutical composition described herein can be used dividually or in same preparation jointly with one or more other medicament.This other medicament comprises for example antihistamine drug, beta-agonists (for example salbutamol), antibiotic, antibiotic medicine (for example ibuprofen, prednisone (corticosteroid) or Pentoxifylline), antifungal drug (for example amphotericin B, fluconazol (Fluconazole), ketoconazole (Ketoconazol) and itraconazole (Itraconazol)), steroid, congested demulcent, bronchodilator etc.Preparation also can contain antiseptic, cosolvent, chemical buffer, surfactant, emulsifying agent, coloring agent, flavour enhancer and sweeting agent.
Pharmaceutical composition described herein can be used for the treatment of the patient who suffers from by the disease of lipoxidase and/or the active mediation of leukotriene.In one embodiment, disease is by 5-and/or the active mediation of 12-lipoxidase.In another embodiment, disease is an inflammatory disease.
Disease by lipoxidase and/or the active mediation of leukotriene includes but not limited to asthma, rheumatic arthritis, gout, psoriasis, allergic rhinitis, respiratory distress syndrome, chronic obstructive pulmonary disease, acne, atopic dermatitis, atherosclerosis, aortic aneurysm, sickle cell disease, acute lung injury, ischemia/reperfusion injury, nasal polyp, inflammatory bowel (comprising for example ulcerative colitis and Crohn disease (Crohn ' s disease)), irritable bowel syndrome, cancer, tumor, respiratory syncytial virus, septicemia, endotoxin shock and myocardial infarction.
In one embodiment, the disease by lipoxidase and/or the active mediation of leukotriene is an inflammatory disease.Inflammatory disease includes but not limited to appendicitis, peptic ulcer, gastric ulcer or duodenal ulcer, peritonitis, pancreatitis, acute or ischemic colitis, diverticulitis, epiglottitis, relaxing can not, cholangitis, cholecystitis, hepatitis, inflammatory bowel (for example comprises Crohn disease (Crohn ' sdisease) and ulcerative colitis), enteritis, Whipple ' s disease, asthma, chronic obstructive pulmonary disease, acute lung injury, intestinal obstruction (comprising for example post operative ileus), anaphylaxis, anaphylactic shock, the immunity complex disease, the organ ischemia, reperfusion injury, organ necrosis, Hay Fever, sepsis, septicemia, endotoxin shock, cachexia, hyperpyrexia, eosinophilic granuloma, granulomatosis, sarcoidosis, septic abortion, epididymitis, vaginitis, prostatitis, urethritis, bronchitis, emphysema, rhinitis, Cystic fibrosis, pneumonia, anthraco-silicosis, alveolitis, bronchiolitis, pharyngitis, pleuritis, sinusitis, influenza, respiratory syncytial virus, herpes, the dispersivity bacteremia, dengue fever, candidiasis, malaria, filaricide, amebiasis, hydatidoma, burn, dermatitis, dermatomyositis, sunburn, urticaria, wart, vesicle (wheal), vasculitis, vasculitis, endocarditis, arteritis, atherosclerosis, thrombophlebitis, pericarditis, myocarditis, myocardial ischemia, arteritis nodosa, rheumatic fever, the A Cihai Mo's disease, coeliac disease, congestive heart failure, adult respiratory distress syndrome, meningitis, encephalitis, multiple cerebral sclerosis, cerebral infarction, cerebral embolism, the Guillame-Barre syndrome, the neuritis, neuralgia, spinal cord injury, paralysis, uveitis, arthritide, arthralgia, osteomyelitis, fascitis, Paget ' s disease, gout, periodontal, rheumatic arthritis, synovitis, myasthenia gravis, thyroiditis, systemic lupus erythematosus (sle), Goodpasture ' s syndrome, Behcet ' s syndrome, allograft rejection, graft versus host disease, type i diabetes, ankylosing spondylitis, Berger ' s disease, type ii diabetes, Retier ' s syndrome or Hodgkins disease.
In another embodiment, inflammatory disease is selected from rheumatic arthritis, asthma, chronic obstructive pulmonary disease, acute lung injury, inflammatory bowel, anaphylaxis, organ ischemia, reperfusion injury, rhinitis, dermatitis, atherosclerosis, myocardial ischemia and adult respiratory distress syndrome.
Embodiment 1: solubility study
Measured zileuton at the dissolubility during at 5 and 25 ℃ under the situation that has the CAPTISOL cyclodextrin.With a series of CAPTISOL cyclodextrin solutions of the excessive zileuton of molal quantity (100mg/mL, or 423mM) balance (100 arrive 400mg/mL, or about 45 arrive 182mM).(seeing table).Preferably solution is buffered to pH5.5 with the 10mM citrate buffer agent.
Drug level (mg/mL) CAPTISOL cyclodextrin concentration (mg/mL)
100 Do not have
100 25
100 50
100 100
100 250
100 300
100 350
100 400
These mixture were stirred for 1 week at 5 ℃ then by ultrasound waveization.Another group is equally according to the sample of top description preparation, in temperature-controlling chamber in 25 ℃ of stirrings.
After the balance through 1 week, each sample is centrifugal, by the drug level in the simple UV check and analysis supernatant.By the molar solubility of zileuton in each sample is mapped to the concentration of CAPTISOL cyclodextrin, compound stoichiometry (for example 1: 1 or 1: 2) and binding constant K have been determined.For 1: 1 complex, equation was [Higuchi T, Connors KA. phase solubility technology (Phase-solubility techniques) Adva AnalChem Instr.1965; 4:212-217]:
S = S 0 + KS 0 1 + KS 0 C T
S combines and unconjugated total drug solubility C with cyclodextrin TBe cyclodextrin concentration total in the sample, S 0Be the intrinsic solubility (dissolubility when not having cyclodextrin) of medicine, K is 1: 1 o'clock a binding constant.According to slope and S 0Value, can determine K.The result of this analysis is mapped in Fig. 2, and 1: 1 binding constant is about 3,200 when showing 25 ℃.The molar ratio of (25 ℃) cyclodextrin and medicine is about 1.7: 1 when solubility limit.
Embodiment 2: stability and coerce (stress) test
Carried out the stability of feasibility study with investigation zileuton-cyclodextrin solution of preparation under three kinds of different initial pH value (about 4.0,5.5 and 7.0).Solution is formulated into and contains 15mg/mL zileuton, 250mg/mL CAPTISOL cyclodextrin and 10mM citrate buffer agent.Coerce test by sample being carried out 1 time and 3 freeze-thaw cycle carry out under every kind of pH value.In addition, the sample under every kind of pH value is stored in 5 ℃, 25 ℃ and 40 ℃ 8 weeks altogether.At each test interval, the pH of visual inspection sample and analytic sample, osmotic pressure, color and medicine usefulness.
With suitable buffer agent, being preferably the 10mM citrate buffer agent, to have prepared pH be zileuton-CAPTISOL cyclodextrin formulations of containing 15mg/mL medicine and 250mg/mL CAPTISOL cyclodextrin of 4,5.5 and 7, and stored for 8 weeks at 5 ℃, 25 ℃ and 40 ℃.Data [Alvarez, FJ according to document; Slade, RT. zileuton---the degradation kinetics and mechanism (the Kinetics and mechanism of degradation of zileuton of potential 5-lipoxygenase inhibitor, a potent 5-lipoxygenase inhibitor.) Pharm.Res., 1992,9 (11): 1465-1473], estimate zileuton in the scope of pH4 to 7, in solution, have enough short-term stabilities (25 ℃ at least 1 month).
Is 1 liter by add distilled water in the 1.9212g anhydrous citric acid to final volume, has prepared 10mM citric acid buffer agent liquid storage (A).By at 2.9411g Sodium Citrate, usp, Dihydrate Powder (Na 3C 6H 5O 7.2H 2O) adding distilled water in is 1 liter to final volume, has prepared 10mM sodium citrate buffer agent liquid storage (B).
Above-mentioned buffer agent liquid storage A and B merging have been prepared the buffer solution that is used for every kind of preparation, shown in following table 3:
Table 3: the preparation of buffer solution
Buffer agent Citric acid (mL) Sodium citrate (mL) The pH that measures
The 10mM citrate, pH4.0 ± 0.2 Quantitatively to 200mL 72 3.94
The 10mM citrate, pH5.5 ± 0.2 58 Quantitatively to 200mL 5.47
The 10mM citrate, pH7.0 ± 0.2 6 Quantitatively to 200mL 6.97
Buffer solution preparation above using then is approximately pH4.0, three kinds of solution of 5.5 and 7.0.Three kinds of all solution all contain 15mg/mL zileuton and 250mg/mL CAPTISOL cyclodextrin.Add and dissolving zileuton and CAPTISOL cyclodextrin (and at pH5.5 and 7.0 o'clock sodium hydroxide) afterwards, but before finishing final dilution step, the pH that carries out solution measures.Solution is sucked in the brown glass bottle, with rubber stopper and the sealing of aluminum closing in medicated cap.In order to carry out effect test, dress 2mL solution in the bottle is for pH, osmotic pressure, color and range estimation detection, the 10mL solution of packing into.In addition, the 10mL that packs in the brown glass bottle is used to coerce test (freeze thawing).All bottles are stored in the temperature-controlled box of 5 ℃, 25 ℃ and 40 ℃.
The sucking-off sample is tested 0 o'clock, 1 week, 2 weeks, when 4 weeks and 8 weekly intervals.
Coerce test (freeze thawing)
To be used for bottle that 1 and 3 circulation coerce test be stored in-20 ℃ about 24 hours, be placed on then in 25 ℃ of apothecas about 1 hour 20 minutes, at this moment sample melts.Test pH, osmotic pressure, color, range estimation detection and usefulness that 1 circulation is coerced sample then.3 circulation are coerced sample and are taken back in-20 ℃ of casees about 24 hours, melt about 1 hour at 25 ℃ then.Sample is put back in-20 ℃ of casees about 26.5 hours, melted about 3 days at 5 ℃ then, test pH, osmotic pressure, color, range estimation detection and usefulness then.
Usefulness, pH, range estimation detection, osmotic pressure and color measurement result that 1 circulation and 3 circulating freezing resistances are coerced test are presented among the table 4-6.
Data are coerced in the freeze thawing of table 4:pH4.0 solution
Test interval Usefulness (mg/mL) The pH that measures Range estimation Color (KSU) Osmotic pressure (mOsmol/kg)
0 o'clock 15.14 4.06 By 0 864
1 circulation 14.58 4.07 By 20 862
3 circulations 15.21 4.05 By 16 868
Data are coerced in the freeze thawing of table 5:pH5.5 solution
Test interval Usefulness (mg/mL) The pH that measures Range estimation Color (KSU) Osmotic pressure (mOsmol/kg)
0 o'clock 14.64 5.61 By 19 852
1 circulation 14.46 5.54 By 19 857
3 circulations 14.60 5.47 By 19 864
Data are coerced in the freeze thawing of table 6:pH7.0 solution
Test interval Usefulness (mg/mL) The pH that measures Range estimation Color (KSU) Osmotic pressure (mOsmol/kg)
0 o'clock 14.51 6.93 By 15 863
1 circulation 14.41 6.94 By 15 860
3 circulations 14.55 6.97 By 17 866
Usefulness, pH, color and the osmotic pressure of 1 circulation and 3 circulating freezing resistance samples do not show obvious variation.In addition, in any sample, observe tangible special feature by the range estimation detection.Therefore, all sample all shows freezing and to melt coercing of bringing be stable.
Sample stores the stability in 8 weeks in temperature-controlling chamber
Interim when the storage in 8 weeks, all 5 ℃ and 25 ℃ of samples all do not show tangible usefulness and change, the pH that only shows slightly changes, and this has proved these preparations stability between the whole storage life under 5 ℃ and 25 ℃ of conditions.The osmotic pressure data show that the osmotic pressure of these preparations is to 903mOsmol/kg from 843.
Embodiment 3
The purpose of this research is to be evaluated at (10mg/mL zileuton, 167mg/mL CAPTISOL cyclodextrin) under lower medicine and the cyclodextrin level, with the buffered stability that is adjusted to zileuton-cyclodextrin solution of initial target pH4.0 of 10mM citrate.
By 417g CAPTISOL cyclodextrin is dissolved in the citrate buffer of about 1.75L 10mM, prepared cyclodextrin solution.Weighing 25g zileuton is transferred in the cyclodextrin solution while stirring.After finishing dissolving, measure the pH of preparation and turn out to be pH4.0.Then with citrate buffer with solution dilution, make that the final volume of solution is 2.5L.From solution, get the five equilibrium sample and measure pH, and be confirmed that it is 4.0.
Prepared the contrast solution that does not contain medicine by similar blend step.
To test and the control formulation vial of packing into, be stored in 5 ℃, 25 ℃ and 40 ℃.0 o'clock, 2 weeks, January and March at interval the sucking-off sample test.Usefulness, pH, range estimation detection, osmotic pressure (only at 0 o'clock) and color are tested.Also carried out grading analysis at each interval with instrument.
Data show, through 3 months, do not show the variation of tangible levels of drugs at the sample of 5 ℃ and 25 ℃ storages.The range estimation of sample detects and shows there be not being separated of visible precipitation or other.The grain count of carrying out with instrument has confirmed that the counting of every mL in the solution unit of all tests is at present within the USP instrument granule limited field to 30mL small size injection (SVI) solution.The osmotic pressure of 0 o'clock preparation is 529mOsmol/kg.
Embodiment 4: the stability of zileuton-CAPTISOL cyclodextrin formulations after lyophilization is dissolved then again
The purpose of this research is to determine to have carried out cryodesiccated zileuton-cyclodextrin formulations (15mg/mL zileuton, 250mg/mL CAPTISOL cyclodextrin, stability pH4).The lyophilization bottle of zileuton-cyclodextrin formulations is dissolved again and is analyzed, with the character of the determining solution function as concentration.In addition, dissolved again bottle is stored in two kinds of following two time points of temperature, with the research stability of dissolved solution again.Sample is estimated detection, and analyzes pH, osmotic pressure, color and usefulness after the dissolving again.After dissolving again immediately and after 5 ℃ and 25 ℃ store 8 and 24 hours, carry out the instrument granule and measure, to seek sedimentary evidence.The lyophilization bottle 5 ℃ store about 6 months after repeated trials.
Cryodesiccated bottle sample is dissolved as 10,15 and 20mg/mL again with the diluent of five equilibrium, detects usefulness, pH, osmotic pressure, color then, and estimates detection.Again dissolved bottle is also carrying out the instrument grain count after the dissolving again immediately and after 5 ℃ and 25 ℃ store 8 and 24 hours.Again dissolving used filterable distilled water to carry out.
Carried out another test period after about 6 months at interval at cryodesiccated bottle 5 ℃ of storages.Use filterable distilled water to be dissolved into 15mg/mL again bottle, detected usefulness, pH, osmotic pressure, color then, and the range estimation outward appearance.Also bottle has been carried out instrument grain count inspection.
The result of usefulness, pH, range estimation detection, osmotic pressure and color measurement is presented among the table 7-10.
Table 7: with the 15mL diluent result of dissolved sample again (zero-time at interval)
Sample Usefulness (mg/mL) pH Range estimation Color (ks) Osmotic pressure (mOsmol/kg)
15-A 15.4 4.01 By 10.0 960
15-B 17.6 4.05 By 7.0 967
15-C 15.0 4.07 By 10.0 976
Table 8: with the 20mL diluent result of dissolved sample again (zero-time at interval)
Sample Usefulness (mg/mL) pH Range estimation Color (ks) Osmotic pressure (mOsmol/kg)
20-A 11.5 3.98 By 6.5 693
20-B 11.7 3.98 By 7.0 696
20-C 11.4 3.97 By 9.5 693
Table 9: with the 30mL diluent result of dissolved sample again (zero-time at interval)
Sample Usefulness (mg/mL) pH Range estimation Color (ks) Osmotic pressure (mOsmol/kg)
30-A 8.1 3.99 By 4.0 447
30-B 8.0 4.00 By 3.5 447
30-C 8.5 3.98 By 5.0 447
Table 10: with the 20mL diluent result of dissolved sample again (6 months at interval)
Sample Usefulness (mg/mL) pH Range estimation Color (ks) Osmotic pressure (mOsmol/kg)
20-A (6 months) 12.26 4.15 By 17 687
20-B (6 months) 12.32 4.16 By 15 688
20-C (6 months) 12.20 4.16 By 17 687
The concentration of zileuton after considering the volume that lyophilization thing (medicine and CAPTISOL cyclodextrin) is occupied, conforms to dilution factor in dissolved sample again.Again the pH data of dissolved bottle show that the pH of all solution is 4.0 ± 0.1 after dissolving again.The osmotic pressure data show goes out the increase (reducing of diluent volume) along with formulation concentrations, and osmotic pressure increases.
Store that the efficiency value of dissolved sample is consistent with stable product again after 6 months.The unconspicuous change that the pH data show at 6 months intervals goes out pH.Osmotic pressure data and zero-time data consistent at interval.
All bottles have all passed through range estimation and have detected.The instrument grain count of the every mL of all specimen is at present injects within the USP granule limited field of (SVI) solution the 20mL small size.
Although invention has been described with reference to some preferred embodiment, these preferred embodiments do not plan by any way scope of the present invention to be construed as limiting.The equivalent that scope of the present invention is authorized by following claim and their all laws defines.

Claims (54)

1. the bag that contains lipoxygenase inhibitor and cyclodextrin is replied the pharmaceutical composition of compound by letter, and wherein lipoxygenase inhibitor exists to treat effective concentration in compositions.
2. the pharmaceutical composition of claim 1 also comprises pharmaceutically useful excipient.
3. the pharmaceutical composition of claim 1, lipoxygenase inhibitor wherein is selected from the inhibitor of 5-lipoxygenase inhibitor, 12-lipoxygenase inhibitor and 5-and 12-lipoxidase.
4. the pharmaceutical composition of claim 3, cyclodextrin wherein is selected from alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin and derivant thereof.
5. the pharmaceutical composition of claim 4, lipoxygenase inhibitor wherein is the 5-lipoxygenase inhibitor.
6. the pharmaceutical composition of claim 5, cyclodextrin wherein is the beta-schardinger dextrin-or derivatives thereof.
7. the pharmaceutical composition of claim 3, lipoxygenase inhibitor wherein has structural formula (II):
Figure A2006800426100002C1
R wherein 5Be C 1Or C 2Alkyl or NR 6R 7, R wherein 6And R 7Be independently selected from H and C 1Or C 2Alkyl; B is CH 2Or CHCH 3W is oxygen or sulfur.
8. the pharmaceutical composition of claim 7, cyclodextrin wherein is selected from the beta-schardinger dextrin-of 2-hydroxypropyl-beta-schardinger dextrin-and sulfo-butyl derivatization.
9. the pharmaceutical composition of claim 8, lipoxygenase inhibitor wherein has structural formula (III):
Figure A2006800426100003C1
10. the pharmaceutical composition of claim 9, beta-schardinger dextrin-wherein is sulfo-butyl ether (7)-beta-schardinger dextrin-.
11. the pharmaceutical composition of claim 10, wherein the concentration of lipoxygenase inhibitor from about 0.1mg/mL to about 200mg/mL.
12. the pharmaceutical composition of claim 12, wherein the concentration of lipoxygenase inhibitor from about 5mg/mL to about 50mg/mL.
13. the pharmaceutical composition of claim 12, wherein the molar ratio of lipoxygenase inhibitor and cyclodextrin is from about 10: 1 to about 1: 10.
14. the pharmaceutical composition of claim 13,5-lipoxygenase inhibitor wherein exists with the concentration from about 0.1mg/mL to about 200mg/mL, and cyclodextrin exists with the concentration from about 10mg/mL to about 500mg/mL.
15. the pharmaceutical composition of claim 14 also contains buffer agent.
16. the pharmaceutical composition of claim 15, buffer agent wherein is a citrate buffer agent.
17. the pharmaceutical composition of claim 16, wherein the concentration of citrate buffer agent from about 5mM to about 500mM.
18. the pharmaceutical composition of claim 17 has from about 3 to about 9 pH value.
19. the pharmaceutical composition of claim 18, quilt is prepared is used for parenteral.
20. the bag that contains lipoxygenase inhibitor and cyclodextrin is replied the parenteral administration of compound by letter, lipoxygenase inhibitor wherein exists to treat effective concentration.
21. the parenteral administration of claim 20, lipoxygenase inhibitor wherein are the 5-lipoxygenase inhibitor, and cyclodextrin is the beta-schardinger dextrin-or derivatives thereof.
22. the parenteral administration of claim 21, the 5-lipoxygenase inhibitor wherein and the molar ratio of beta-schardinger dextrin-were from about 10: 1 to about 1: 10.
23. the parenteral administration of claim 22, the concentration of 5-lipoxygenase inhibitor wherein from about 0.1mg/mL to about 200mg/mL, and the concentration of beta-schardinger dextrin-from about 4mM to about 900mM.
24. to about 50mg/mL, and beta-schardinger dextrin-exists with the concentration from about 20mM to about 500mM from about 5mg/mL for the parenteral administration of claim 23, the concentration of 5-lipoxygenase inhibitor wherein.
25. the parenteral administration of claim 24 also contains buffer agent.
26. the parenteral administration of claim 25, buffer agent wherein are the citrate buffer agent that exists with the concentration from about 5mM to about 500mM.
27. the parenteral administration of claim 26,5-lipoxygenase inhibitor wherein exists with the concentration from about 0.1mg/mL to about 200mg/mL, beta-schardinger dextrin-exists with the concentration from about 10mM to about 500mM, citrate buffer agent exists with the concentration from about 5mM to about 15mM, and parenteral administration wherein has from about 3 to about 9 pH value.
28. the parenteral administration of claim 27, beta-schardinger dextrin-wherein are selected from the beta-schardinger dextrin-of 2-hydroxypropyl-beta-schardinger dextrin-and sulfo-butyl derivatization, and the 5-lipoxygenase inhibitor has structural formula (III):
Figure A2006800426100005C1
29. the bag that contains lipoxygenase inhibitor and cyclodextrin is replied the drying agent of compound by letter, bag is wherein replied compound by letter and is had the dissolubility of 0.2mg/mL at least, and lipoxygenase inhibitor exists to treat effective concentration.
30. the drying agent of claim 29, lipoxygenase inhibitor wherein are the 5-lipoxygenase inhibitor, and cyclodextrin is a beta-schardinger dextrin-.
31. the drying agent of claim 30, beta-schardinger dextrin-wherein are selected from the beta-schardinger dextrin-of 2-hydroxypropyl-beta-schardinger dextrin-and sulfo-butyl derivatization, and the 5-lipoxygenase inhibitor has following structural:
Figure A2006800426100005C2
32. the drying agent of claim 31 also contains buffer agent.
33. the drying agent of claim 32, wherein after the dissolving of use diluent, the concentration of 5-lipoxygenase inhibitor is to about 200mg/mL from about 0.1mg/mL.
34. the drying agent of claim 33 is applicable to oral, per rectum, per nasal, through lung, through eye, transvaginal, through ear, part, in cheek, transdermal, intravenous, intramuscular, subcutaneous, intradermal, ophthalmic, brain, in the lymph gland, in the intraarticular, sheath or the intraperitoneal administration.
35. the drying agent of claim 29, wherein said preparation prepares by the method that is selected from lyophilization, spray drying and supercritical extraction.
36. the bag that contains lipoxygenase inhibitor and cyclodextrin is replied the compositions of compound by letter.
37. the compositions of claim 36, lipoxygenase inhibitor wherein have molecular formula (II):
Figure A2006800426100006C1
38. the compositions of claim 37, cyclodextrin wherein is selected from alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin and derivant thereof.
39. the compositions of claim 38, cyclodextrin wherein are the beta-schardinger dextrin-or derivatives thereofs.
40. the compositions of claim 38, cyclodextrin wherein are selected from the beta-schardinger dextrin-of 2-hydroxypropyl-beta-schardinger dextrin-and sulfo-butyl derivatization.
41. the bag of making lipoxygenase inhibitor and beta-schardinger dextrin-is replied the method for the aqueous solution of compound by letter, comprises the following steps:
A. prepare aqueous buffer;
B. beta-schardinger dextrin-is dissolved in the buffer solution; And
C. lipoxygenase inhibitor is joined in beta-schardinger dextrin-and the buffering solution to produce its mixture.
42. the method for the manufacturing aqueous solution of claim 41 comprises that also mixture to lipoxygenase inhibitor and beta-schardinger dextrin-stirs and/or the step of ultrasound waveization.
43. the method for the manufacturing aqueous solution of claim 41 comprises that also the pH with buffer solution adjusts to from about 3 to about 9 step.
44. the method for the manufacturing aqueous solution of claim 42, solution wherein has the 5-lipoxygenase inhibitor of concentration from 0.1mg/mL to about 200mg/mL, the beta-schardinger dextrin-of concentration from about 10mM to about 500mM, and buffer agent wherein is the citrate buffer agent that exists with the concentration from about 5mM to about 15mM.
45. the method for the manufacturing aqueous solution of claim 43, beta-schardinger dextrin-wherein are selected from the beta-schardinger dextrin-of 2-hydroxypropyl-beta-schardinger dextrin-and sulfo-butyl derivatization, and the 5-lipoxygenase inhibitor has structural formula (III):
Figure A2006800426100007C1
46. in the mammal of needs treatment, treat the method for the disease of the active mediation of lipoxidase by the disease of the active mediation of lipoxidase, comprise and use the step that the bag that contains lipoxygenase inhibitor and cyclodextrin is replied the preparation of compound by letter, wherein said preparation contains the lipoxygenase inhibitor for the treatment of valid density.
47. the method for claim 46, disease wherein is selected from asthma, rheumatic arthritis, gout, psoriasis, allergic rhinitis, respiratory distress syndrome, chronic obstructive pulmonary disease, acne, atopic dermatitis, atherosclerosis, aortic aneurysm, sickle-cell disease, acute lung injury, ischemia/reperfusion injury, nasal polyp, inflammatory bowel, irritable bowel syndrome, cancer, tumor, respiratory syncytial virus, septicemia, endotoxin shock and myocardial infarction.
48. the method for claim 46, disease wherein is an inflammatory disease.
49. the method for claim 46, lipoxygenase inhibitor wherein is selected from the inhibitor of 5-lipoxygenase inhibitor, 12-lipoxygenase inhibitor and 5-and 12-lipoxidase, and cyclodextrin wherein is selected from alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin or derivatives thereof.
50. the method for claim 46, preparation wherein is an aqueous solution, and lipoxygenase inhibitor exists with the concentration from about 0.1mg/mL to about 200mg/mL.
51. the method for claim 46, cyclodextrin wherein are selected from the beta-schardinger dextrin-of 2-hydroxypropyl-beta-schardinger dextrin-and sulfo-butyl derivatization, and lipoxygenase inhibitor has structural formula (III):
52. the method for claim 51, preparation wherein passes through parenteral.
53. the method for claim 52, preparation wherein are the lyophilization things.
54. the method for claim 53, preparation wherein passes through oral administration.
CNA2006800426101A 2005-11-15 2006-11-15 Compositions comprising lipoxygenase inhibitors and cyclodextrin Pending CN101309707A (en)

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